I have read with great interest the data presented by Doyle et al.1 on the new adjuvant immunotherapy-based treatment involving clinical deployment of IL-18 for neovascular age-related macular degeneration (AMD). The data in their study are displayed elegantly with convincing results, in spite of the contrasting opinions presented in another study.2 I applaud their interesting and important work, but I believe that some concerns need to be addressed.

First, the authors found that IL-18 treatment inhibited VEGFR-2 expression, which would effectively reduce VEGF signal transduction. However, the mechanism of antiangiogenesis of IL-18 is still poorly understood. In addition, this study shows that IL-18 could not be used as a major agent to treat choroidal neovascularization (CNV) in AMD, because IL-18 activity in reducing leakage was not as pronounced as that of Lucentis (Novartis Pharma AG, Basel, Switzerland). Do these findings mean that IL-18 can be just used in adjunct immunotherapy alongside current anti–VEGF-based strategies for the treatment of CNV in the future? Plus, the authors found that IL-18 treatment works more effectively in combination with anti-VEGF therapy in their recently published study3; what if it works in combination with anti-VEGF agents in nonhuman primates? Unfortunately, the authors did not show the data, but I believe the results would be of great interest to the readers and may have important clinical significance.

Second, in their previous study,3 the authors found that IL-18 can be administered systemically, for example, subcutaneously, while still affecting the eyes of C57BL/6J mice. These findings should be confirmed in primates in a preclinical study. Systemic administration may give IL-18 a big advantage over the other anti-VEGF drugs that can only be administrated intravitreally (IVT). Of course, it is possible that the authors are already conducting these studies, and I look forward to seeing the results.

Third, the authors have only studied the effect of IL-18 in CNV induced by laser burn. Considering the mechanism of antiangiogenesis induced by IL-18, do you think it will be efficacious in other types of neovascular ocular diseases, such as proliferative diabetic retinopathy (PDR) and neovascularization induced by retinal vein occlusion (RVO)? In a previous study,4 some authors reported that both intravitreous IL-18 and VEGF levels were elevated in patients with PDR, and were closely correlated in active PDR. It seems that IL-18 may contribute to retinal angiogenesis by acting together with or via VEGF in patients with PDR. This is very puzzling when compared with the results,1,3,5 because of the reciprocal suppression between IL-18 and VEGF on retinal and choroidal vasculature.6 How do we explain this discrepancy?